LOCAL  ANESTHETICS 


BY 

FRANK  LOUIS  ROMAN 

B.S.  University  of  Illinois,  1911 


THESIS 

SUBMITTED  IN  PARTIAL  FULFILLMENT  OF  THE  REQUIREMENTS 
FOR  THE  DEGREE  OF  MASTER  OF  SCIENCE  IN  CHEMISTRY 
IN  THE  GRADUATE  SCHOOL  OF  THE  UNIVERSITY 
OF  ILLINOIS,  1922 


URBANA,  ILLINOIS 


Digitized  by  the  Internet  Archive 
in  2016 


https://archive.org/details/localanestheticsOOroma 


I wish  to  extend  my  sincere  thanks  to  Professor  Koger  Adams 
for  his  many  suggestions  and  kind  interest  during  the  investigations 
which  are  here  described. 


TABLE  OF  CONTESTS 


Part  I 

Preparation  of  Compounds  of  the  Type 

0 Rl  H 

p-nh2-c6h4-c  -o-9  - ch2  - n -tc2Hg)2 1 

Rg  01 

Theoretical  Part 1 

Experimental  Part... ••••••••••• 3 

Preparation  of  diethylaminoacetone.... ..3 

" " diethylaminodimethylethylcarbinol..... .4 

" " the  nitro  ester 5 

Reduction  of  the  nitro  ester. •••••• 5 

Preparation  of  the  monoohlorhydrate 5 

rt  ” diethylaminotertiarybutylparaaminobenzoate- 

mono  chi  or  hydrate 6 

" " monochlor tertiary  alcohols 7 

Part  II 

The  Structure  of  the  Compounds  Produced  fromOlefines  and  Mercuric 

Salts.  Mercurated  Benzofurans  ..••..•••.8 

Theoretical  Part 8 

Experimental  Part 11 

Preparation  of  Phenyl  Allyl  Ether............ 11 

Rearrangement  of  phenyl  allyl  ether  to  ortho  allyl  phenol. .11 

Preparation  of  chloromercuri-l-methylbenzofuran 11 

" **  bromomercuri-l-methylbenzofuran 12 

M **  mercuric  sulphate  derivatives  of  ortho 

allyl  phenol. 13 

Reduction  of  Chloromercuri-l-methylbenxofuran  to 

dibenzofuryl-l-methylnercury 15 

Arsenic  chloride  - ortho  allyl  phenol  addition  products. ...  17 

Bibliography •••••••••••• •••••• ••••••..••19 


Part  I 


Preparation  of  Compounds 
of  the  Type 


9 ft  ? 

p-HH2  -C6H4  - C -0-  9 -CH2-N(C2H5)2 

% 


Cl 


Theoretical  Part, 


Because  of  their  value  as  local  anesthetics,  the  compounds  of  the 
0 H 

type  p~HH2-C6H4-C-0(CH2)x-N=E2  have  been  the  subject  of  considerable  study 

/i  o) 

during  the  last  few  years.  The  best  known  of  these  compounds  is  novocaine' J■»c, 

9 ? 

or  procaine,  its  chemical  constitution  being  NH2-C5H4-C-O-CH2-CH2  -N*(C2Hg)2* 

C 1 

diethylaminoethylparaaminobenzoatemonochlorhydrate.  The  corresponding 


dinormalbutylaminopropylparaaminobenzoatemonochlorhydr&te: 

0 H 

ira2"°6H4  ” G - 0 -C  H2  ~C  H2-CH2  - 

is  known  as  butyn^J*  The  compounds  of  the  two  types: 

0 H 

KH2-C  6H4-C-0-CH2-CH2-N=B2 

Cl 

9 H 

nh2  - c6h4  - c-o-ch2-ch2-ch2  -h=h2 

were  the  subject  of  extensive  studies  by  Jenkins^),  Burnett^,  and  Peet.^ 
To  complete  these  studies  it  was  necessary  that  the  corresponding 
compounds  containing  forked  side  chains  between  the  oxygen  and  the  nitrogen 
be  investigated,  and  it  was  the  object  of  the  following  researches  to  prepare 
compounds  of  the  type 


H 

1 


0 ?1 

kh2  -c6%-c-o-c  -ch2  -n=(02h5)2 

Cl 


JL  O 


V.  ' 


j*  i l . : 


y 


j 


. i. 


v 


2 


Attempts  -were  made  to  prepare  first  the  simplest  compounds 

0 CH3  H 

mz  -c6h4  -c  -o  -9  -ch2  - ]jr=(c2H5)2 
ch3  Cl 

9 92H5  ¥ 

-°6H4-  C -0  -C  - CH2-  K=(C2H5)2 


ch3 


Cl 


and  as  the  results  were  unsatisfactory,  the  preparation  of  the  more  complex 
products  was  not  undertaken.  This  investigation  deals  therefore  only  with  the 
preparation  of  the  above  two  compounds. 

There  are  several  methods  for  preparing  the  novocaines^»2 ) , the 
methods  differing  in  general  in  the  order  in  which  the  various  intermediates 
are  combined.  The  method  chosen  for  this  work  comprised  the  following  steps: 

1.  Preparation  of  the  diethylaminoacetone^ 7 ) from  monochloracetone 
and  diethylamine. 

ch3-co-ch2oi+hn(c2h5)2  — 3*  ch3-co-ch2— n(c2h5)2 

2.  Preparation  of  diethylaminotrimethylcarbinol  and  diethylaminodi- 
methylethylcarbinol  from  diethylaminoacetone  and  Grignard  reagent. 

on  hydrolysis  R 


CH3  — C0-CH2-K  ( C2H5 ) 2 +R  Mg  Br 


►ho-6  — ch2-n(c2h5)2 
ch3 


3.  Preparation  of  nitro  esters  from  paranitrobenzoylchloride  and  the 
above  tertiary  alcohols. 


R 


P R 


H 


R°2-C6H4-C  -Cl  + HO  -C — CH2-N(C2H5)2 •iT02-C6H4-C-0-C — CH2-N=(C2H5)2 


CR 


6h3  Cl 


4.  Reduction  of  the  nitroesters 

Pe 


0 R 

II  I 


OR  H 

N°2-C6H4-C-0-C  — CHg-N  (C2H5)2i-^-^ini2^6H4-C-0-C^CH  -N(C2H5)2 
CE3  Cl  CH3 


5.  Preparation  of  the  hydrochloride  by  neutralizing  with  alcoholic 


HC1. 


3 


9 ? HCl  0 R H 

HH2-C6B4-C-0-C-CH2-N(C2H5)2  — > HHg-CgH.-C  -0-C  -CE,  - N (C.HJ. 

oh3  ch3  Cl  2 

The  following  modification  of  the  above  method  was  also  tried: 

1*  Preparation  of  the  monochlortrialkyl  carbinol  from  monochloracetone 
and  Grignard  reagent. 

CHg-CO-C^-Cl  + RMgBr  — HO  -C  — CH2C1 

ch3 

2.  Preparation  of  the  diethylamine  derivative  of  the  above  product 
R R 

HO  - 6 — CH  -Cl  ♦ N(C2H5)2  ^ HO  - C — CHg  -N(C£H5)2 

ch3  ch3 

Prom  this  point,  the  steps  were  the  same  as  outlined  for  the  first 

method. 

Fairly  good  yields  of  the  diethylaminotertiary  alcohols  were  obtained, 
but  esterification  of  these  alcohols  with  paranitrobenzoyl  chloride  gave  poor 
yields.  These  esters  decomposed  readily,  even  on  slight  warming  in  benzene, 
and  on  reduction  and  neutralization  of  the  resulting  amino  esters  syrupy  pro- 
ducts were  formed.  Attempts  to  crystallize  these  products  from  absolute  alcohol 
yielded  only  a few  crystals. 

Experimental  Part 

Preparation  of  diethylamino  acetone ^ 7 ^ 

Thirty-four  grams  of  chloracetone  were  added  slowly  to  54  grams  of 
diethylamine  in  200  cc  of  ether.  The  mixture  was  then  heated  under  reflux  for 
three  hours,  a heavy  crop  of  crystals  being  formed.  After  standing  for  24  hours 
the  mixture  was  filtered,  and  the  crystals  of  diethylamino  hydrochloride  on 
filter  were  washed  with  ether.  Yield  of  diethylaminohydrochloride  - 32  grams 
of  snow  white,  large,  flaky  crystals. 

The  filtrate  and  washings  were  distilled  under  reduced  pressure,  the 
portion  distilling  at  55  to  70®C  at  14  - 25  mm  being  collected.  This  fraction 


. 


. 


...  • ., 
r . 1 


■ ■ ff  . 

• , 

' 


T 


was  redistilled,  the  portion  boiling  at  58  to  65°C  at  14  - 20  nun  being  collected 
Yield,  34  grains  (72$)  of  light  yellow  liquid,  with  properties  corresponding  to 
those  of  die thy laainoace tone. 


Mg  turnings  were  placed  in  a 1 liter  flask  and  200cc  of  dry  ether  added.  The 
flask  was  connected  with  a reflux  condenser  provided  with  a calcium  chloride 
tube.  The  flask  was  placed  in  a pan  of  cold  water  and  29  grams  of  ethylbromide 
were  added  through  the  condenser.  The  reaction  was  slow  and  the  water  bath 
we-s  warmed  gently.  When  the  magnesium  had  nearly  all  dissolved,  the  ether 
mixture  was  boiled  for  2 hours. 


to  prepare  the  diethyl  amino  dimethyl  ethyl  carbinol.  The  flask  was  cooled, 
the  water  bath  being  replaced  by  an  ice  bath.  34  grams  of  diethylamino  acetone 
were  then  added  very  slowly,  froma  dropping  funnel,  through  the  condenser. 

Each  drop  caused  a very  violent  reaction  at  first,  and  constant  cooling  was 
necessary.  A yellow  precipitate  formed  after  about  one-half  of  the  diethyl 
amino  acetone  had  been  added.  The  dropping  funnel  and  condenser  were  finally 
washed  with  ether  and  the  mixture  in  flask  boiled  for  one  hour.  The  mixture 
was  then  allowed  to  stand  until  the  next  day. 


The  Grignard  reagent  obtained  in  the  ether  solution  was  used  as  such 


The  addition  product  formed  was  hydrolysed  with  chips  of  ice 


A concentrated  solution  of  fifty  grams  of  ammonium  chloride  was  added  to  dis- 
so ve  the  magnesium  hydroxide  formed.  The  addition  product  was  sticky  and 
dissloved  only  slowly. 


. 

O'  . ..  - ' I 


. 

. . . V 


. 


j • L'  . ' - 


..  ' . . I 


. 


. I .. 


. . I • . 

■:  ■ . , ■ ■ c • • . i ■ 

• - • 

v.-  : : 


. 


: i - r.  . 


— . — — 


; • f : ' ' •»  * 

. ■ 


5 


The  ether  layer  was  separated  from  the  water  solution  and  dried 
over  night  over  anhydrous  sodium  sulphate.  The  ether  was  then  distilled  off 
and  the  residue  distilled  under  diminished  pressure.  The  distillate  which 
came  over  at  76  to  86#C  at  14  to  20  mm  was  taken  as  diethyl  amino  dimethyl- 
ethyl  carbinol.  Yield  17.5  grams  (42$). 

Preparation  of  the  Nitro  Ester. ( 2 ^ 

Seven  grams  of  diethylamlnodimethylethylcarbinol  and  8.5  grams  of 
para  nitrobenzoylchloride  were  dissolved  separately  in  the  smallest  possible 
quantities  of  benzene.  The  solutions  were  brought  to  room  temperature  and 
mixed  within  a few  minutes  with  constant  stirring.  The  mixture  was  kept  on 
ice  and  the  white  precipitate  which  had  formed  was  filtered  off  within  twenty 
minutes.  Cooling  and  filtration  within  a short  time  were  found  to  be  essential, 
as  decomposition  would  otherwise  occur,  yielding  a dark  precipitate  and  finally 
a tarry  mass.  Yield  of  nitro  ester,  5+  grams,  or  30+$  of  theory.  Attempts  were 
made  to  recrystallize  the  diethylaminodimethylethylcarbinolparanitrobenzoate- 
monoohl or hydrate  thus  obtained  but  without  success,  as  even  slight  warming  in 
benzene,  acetone  or  ethyl  acetate  caused  decomposition  of  the  nitro  ester.  The 
original  product  obtained  was  white,  however,  and  of  apparently  good  quality. 

It  melted  with  decomposition  at  about  160*0. 

Reduct  ion  of  the  Nitro  Ester^ 4 ^ 
and 

Preparation  of  the  Monoohlorhydrate 
The  reduction  of  the  nitro  ester  was  carried  on  by  means  of  iron 
dust  and  water,  the  HC1  in  combination  with  the  nitro  ester  being  sufficient 
to  produce  the  reaction.  Only  enough  water  was  used  to  produce  a thick  paste 
and  the  weight  of  iron  dust  used  was  about  three  times  that  of  the  nitro  ester. 


, 

. 


. 


. • 


. 


, 


, 

. 

, ] i ■ ■ . 


...  , . ■ 


6 


The  reaction  evolved  considerable  heat,  and  the  container  was  cooled  with  ice, 
or  chips  of  ice  were  added  to  the  mixture  whenever  necessary  in  order  to  keep  the 
temperature  below  boiling.  When  evolution  of  heat  had  ceased,  the  mixture  was 
heated  on  a water  bath  for  one-half  hour  to  assure  completion.  Two  methods 
were  tried  in  extracting  the  amino  ester  from  the  mixture.  In  the  first  method, 
the  mixture  was  made  alkaline  with  NaOH  and  the  ester  extracted  with  ether.  In 
the  second  method,  enough  tartaric  acid  in  water  was  added  to  make  the  mixture 
strongly  acid,  and  the  mixture  filtered  at  once.  The  iron  dust  on  filter  was 
washed  first  with  water  and  then  with  IfaOH  solution.  The  filtrate  was  made  al- 
kaline and  extracted  4 times  with  ether.  The  ether  was  evaporated  off,  leaving 
the  amino  ester. 

Considerable  decomposition  took  place  during  this  reduction,  10  grams 
of  the  diethylaminodimethylethycarbinolparanitrobenzoatemonochlorhydlrate  yield- 
ing only  about  2 grams  (20$)  of  diethylaminodimethylethylcarbinolparaaminobenz- 
ate.  This  amino  ester  was  a viscous  oil  with  strong  characteristic  amine  odor. 

To  prepare  the  monochlorhydrate , the  amino  ester  was  dissolved  in 

N 

absolute  alcohol  and  titrated  with  alcoholic  HC1.  The  resulting  diethyl- 

4 

aminodimethylethylparaaminobenzoatemonochlorhydrate  did  not  crystallize  out  on 
evaporation  of  the  alcohol.  Attempts  were  made  to  recrystallize  this  residue 
by  redissolving  it  in  the  smallest  possible  quantity  of  a hot  mixture  of  equal 
parts  of  absolute  alcohol  and  ethyl  acetate.  Only  a few  crystals  were  obtained 
on  cooling,  however. 

Preparation  of  Diethylaminotertiarybutylparaaminobenzoatemonochlorhydratei^^ 
Attempts  were  made  to  prepare  this  product  by  methods  similar  to 
those  described  in  the  preparation  of  diethylaminodimethylethylcarbinolpara- 
aminobenzoatemonochlorhydrate.  The  steps  involved  included: 

1.  The  preparation  of  diethylaminoacetone  as  already  given. 


• \ 


/ • -J  ■. 

-i  ••  “ i r»  .-■*  . . . 

. ' t r : 

. . ,i  . :r  . ’>  ,« 

i ... 


7 

2.  The  preparation  of  the  diethylaminotrimethylcarbinol'  ' from 
diethylaminoacetone  and  Grignard  reagent  CH3  Hgl. 

5.6  grams  magnesium,  33,1  grams  methyl  iodide  and  30  grams  of 
diethylaminoacetone  yielded  8.5  grams  of  diethylaminotrimethylcarbinol,  or 
about  25$  of  the  theoretical  quantity.  This  product  was  nearly  colorless  and 
distilled  at  55  - 60#C  at  15  to  20  mnupressure. 

3.  The  preparation  of  diethylaminotert iarybutylparanitrobenzoate- 
hydrochloride  by  the  method  described  under  "Preparation  of  Nitro  aster." 

15  grams  of  diethylaminotert iarybutylalcohol  yielded  8 grams  of 
the  nitro  ester  (27$  of  theoretical  quantity.)  The  product  was  white  but  some- 
what sticky  and  decomposed  on  heating. 

4.  Seduction  of  the  nitro  ester  and  preparation  of  the  hydrochloride, 
diethylaminotert  iarybutylparaaminobenzoatemonochlorhydrate. 

8 grams  of  the  nitro  ester  yielded  3 grams  of  viscous  amino  ester 

of  light  yellow  color.  The  monochlorhydrate  produced  by  titrating  the  amino 
N 

ester  with  ---  alcoholic  JTC1  until  neutral  to  litmus,  was  of  light  yellow 
color,  somewhat  sticky  and  could  not  be  crystallized. 

Preparation  of  Monochlor  Tertiary  Alcohols. 

Attempts  were  made  to  prepare 

(CH3)2  COH  CH2  Cl<13’14)  and  C2H5  CH3  COH  CH2  Cl{14),  which  on 
treatment  with  diethylamine , would  yield  the  corresponding  diethylamino  alcohols 
Monochlor ace tone  was  treated  with  the  Grignard  reagents,  CH3  Mgl  and  C2HgMgBr 
being  used  for  the  respective  monochlor  tertiary  alcohols.  Addition  with  the 
Grignard  reagent  appeared  to  take  place  satisfactorily,  but  on  hydrolysis  of 
the  addition  products,  only  a few  drops  of  the  corresponding  monochlortertiary 
alcohols  were  obtained. 


- 


. 


. 

. 

. 


. 


. 


. 


. 


. ■ . i • ' 

> 


' I 


8 

Part  II 

The  Structure  Of  the  Compounds  Produced  from  Olefines  and  Mercuric  Salts. 

Mercurated  Benzofurans 

Theoretical  Part. 

The  compounds  produced  from  olefines  and  mercuric  salts  have  been  the 
subject  of  controversy  since  they  were  first  prepared.  Probably  the  most 
generally  accepted  view  is  that  mercuric  salts  form  true  additions  to  the 
ethylene  double  bond,  while  the  opposite  view  is  that  molecular  addition  products 
are  formed. 

Hoffman  and  Sand^5^  first  discovered  that  ethylene  and  mercuric 
salts  would  react,  and  to  the  two  products  obtained  in  aqueous  solution,  they 
gave  the  formulas  HO-C^-CHg-Hg-X  and  X-Hg-CHg-C^-O-C^-C^'Hg-X,  because  when 
treated  with  iodine,  these  two  substances  gave  HO-C^-CHg-I  and  I-CH2" CHg"  0- 
-CH2-CH2-I  respectively,  the  structures  of  which  are  apparently  established. 

They  noted,  however,  that  the  compound  HO-C^-C^-Hg-X  did  not  react  in  the  same 
way  as  the  ordinary  alkyl  mercuric  halides  when  treated  with  alkyl  iodides. 
Ordinary  alkyl  mercuric  halides  are  not  affected  by  boiling  with  alkyl  halides 
while  the  ethylene-mercuric  salt  reaction  products  give  the  reaction: 

H0-CH2-CH2-Hg-X  ♦ SI  s.  0£  % + Hg-X-I  + ROH 

In  addition,  it  was  found  that  the  ethylene-mercuric  salt  reaction  products 
were  decomposed  readily  by  mineral  acids  such  as  HC1,  even  when  a dilute 
solution  of  the  acid  was  used.  A typical  decomposition  is  represented  by  the 
equation: 

H0-CH2-CH2-Hg-Cl  + HC1  ^Hg  Cl2  ♦ HgO  + C2H4 

This  is  quite  different  from  the  action  of  mineral  acids  on  the  simple 
alkyl  mercuric  halides,  which  are  affected  only  by  boiling  with  concentrated 


. 


. 

. 


, 


' 


• V.  ' • 


; . . . • : , ■ ■ 


9 


acid.  To  explain  these  reactions.  Sand  assumed  that  the  product  HO  CHg  CHg  H g X 

could  take  the  tautomeric  form  CHp  « CH2 

^HgtOHlX. 


Mancbot(^)  held  that  the  products  obtained  by  the  action  of  mercuric 
salts  on  olefines  -were  not  double  bond  addition  products  and  that  molecular 
type  products  such  as  °2H4  .Hg  (0H)X  and  2C2H4  .HgO.HgXg  were  actually  formed. 

It  has  been  pointed  out,  however,  that  the  action  of  acids  and  alkyl 
halides  on  the  ethylene-mercuric  salts  reaction  products  might  be  due  merely  to  a 
special  reactivity  of  the  grouping  in  the  true  double  bond  addition  product.  Con- 
siderable evidence  has  been  obtained  in  the  following  investigation  to  show  that 
this  is  actually  the  case. 

Some  insight  in  the  nature  and  structure  of  these  olefine-mercuric 
salt  reaction  produots  could  be  obtained  if  products  could  be  prepared  which 
would  condense  intermolecularly  to  give  new  produots  the  structure  of  which  might 
be  readily  determined.  Orthoallylphenol  gives  with  the  nercuric  salts  condensa- 
tion products  of  this  type,  the  mercurated  benzofurans. 


CH  - CH2 

+ %x2 *► 


OCH2-CHX-CH2HgX 

OH  *» 


CHoCH  CHgHgX 
/ +HX 

0 


These  reactions  take  place  readily  in  aqueous  solutions  at  room  tempera- 
ture, the  chloride,  bromide  and  sulphate  having  been  prepared  during  this  investi- 
gation, while  the  iodide  and  acetate  have  also  been  prepared  by  other  investiga- 
tors. ^ 17  ^ As  might  be  expected,  the  initial  addition  product  is  unstable,  but 
instead  of  hydrolysing  as  the  usual  ethylene-mercuric  salts  addition  products 
according  to  the  equation: 

H20 

CH2=CH2+HgX2 > XCH2CH2HgX  HO  CHg  CHg  HgX  +HX 


the  orthoallylphenol-  mercuric  salt  addition  product  condenses  intermolecularly, 
splitting  off  HX.  That  this  mechanism  is  correct  is  shown  by  the  fact  that  the 


_ _ 


. 


. 

i 

— — 

*■  ' • 


. 


10 


above  reaction  takes  place  in  absolute  alcohol  solution  as  well  as  in  water. (I7) 
In  addition,  the  mercurated  benzofurans  are  formed  in  neutral  and  acid  solutions, 
while  the  preparation  of  the  usual  ethylene -mercuric  salt  addition  products  re- 
quires the  addition  of  alkali  to  neutralize  the  acid  formed.  Sperry( 17 ) found 
that  the  chloromerouri-l-methylbenzofuran  was  not  decomposed  by  20$  HC1  after 
20  hours  at  room  temperature. 

Products  which  are  thought  to  have  been  the  primary  ortho  allyl  phenol- 
mercuric  salt  addition  products  were  found  in  small  quantities  in  some  of  the 
preparations.  They  could  not  be  isolated  in  the  pure  state,  but  when  redissolved 
in  hot  alcohol,  they  yielded  the  corresponding  mercurated  benzofuran,  which 
crystallized  out  on  cooling. 

Further  proof  of  the  structure  of  the  ortho  allyl  phenol  - mercuric 

salt  addition  compounds  was  obtained  by  the  reduction  of  chloro-mercuri-l-methyl 

benzofuran  with  Ha  amalgam  and  treatment  of  the  resulting  product  with  mercuric 

iodide,  yielding  the  iodomercuri-l-methyl  benzofuran.  It  would  be  difficult  to 

explain  these  reactions  if  the  molecular  type  compound  was  assumed  to  be  formed 

by  the  action  of  mercuric  chloride  on  ortho  allyl  phenol.  The  mechanism  of  the 

reaction  is  very  probably  that  shown  by  the  following  equations: 

Ha  amalgam 

2B  HgCl  — E Hg  H ♦ 2 HaCl 

R Hg  R + Hg  Ig  > 2 E Hg  I 

Attempts  were  made  to  obtain  additional  proof  of  the  structure  of 
these  ethylene  addition  compounds  by  preparing  the  arsenic  chloride  - ortho 
allyl  phenol  addition  product.  These  attempts  were  not  successful,  but  this  was 
not  entirely  unexpected  as  Green  and  Priced®)  have  found  that  no  reaction  re- 
sulted when  ethylene  was  passed  in  arsenic  trichloride  under  various  conditions 
of  temperature  and  pressure. 


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11 


Experimental  Part 
Preparation  of  Phenyl  Allyl  Ether 

Phenyl  allyl  ether  was  prepared  according  to  the  method  of  Claisen^19) 

CgHgOH  ♦ CgHgBr  ♦ KgCOg  s*  CgHgO  CSH5+  KBr  + KH  COg 

150  grams  of  phenol,  200  grams  allyl  bromide,  225  grams  potassium  carbonate  and 
150  grams  of  acetone  (as  solvent)  were  placed  in  & round  bottom  flask  fitted 
with  reflux  condenser,  and  the  mixture  heated  on  the  steam  bath  for  10  hours. 

To  follow  the  progress  of  the  reaction,  samples  were  taken  from  time  to  time, 
shaken  with  petroleum  ether  and  1C >$  NaOH  solution.  The  sodium  hydroxide  solu- 
tion was  separated  and  acidified  to  determine  if  phenol  would  still  be  thrown 
out.  Only  a trace  of  phenol  was  found  to  be  present  at  the  end  of  ten  hours. 

Water  and  petroleum  ether  were  then  added  to  the  mixture  in  the  flask, 
the  layers  separated  and  the  petroleum  ether  solution  thoroughly  shaken  with 
sodium  hydroxide  solution,  After  washing  the  ether  layer  with  water,  it  was 
dried  over  anhydrous  potassium  carbonate.  The  ether  was  evaporated  off  and  the 
residue  distilled  under  diminished  pressure.  A yield  of  176  grams  (84$)  of 
phenylallylether , distilling  at  83#C,  under  20  mm  pressure,  was  obtained. 

Rearrangement  of  Phenyl  Allyl  Ether  to  Ortho  Allyl  Phenol^ 2(9,21  ^ 
The  phenyl  allyl  ether  was  refluxed  until  the  temperature,  which 
registered  188*C  at  first,  reached  a constant  point  of  218*0.  The  rearrangement 
was  nearly  quantitative,  the  product  being  practically  pure  ortho  allyl  phenol 
and  requiring  only  a distillation  under  reduced  pressure  for  complete  purifica- 
tion. It  distilled  at  109-110°C  at  22  mm  pressure. 

f 17  \ 

Preparation  of  Chloromercuri-l-methylbenzofuranv  1 
20  grams  of  mercurlcchloride  were  dissolved  in  250cc  of  water  in  a 
500oc  round  bottom  flask  provided  with  a stirring  device.  10  grams  of  ortho 


- 

. 

. 

. 

. . 

. 


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12 


allyl  phenol  were  added  very  slowly  from  a dropping  funnel,  the  time  required 
for  addition  being  about  two  hours,  A voluminous  white  precipitate,  partly 
crystalline,  had  formed,  and  the  mixture  obtained  was  stirred  for  an  additional 
half  hour,  and  allowed  to  stand  over  night. 

The  precipitate  was  filtered  off  and  dissolved  in  hot  alcohol,  from 
which  it  crystallized  on  cooling.  The  chloromercuri-l-methylbenzofuran  thus 
obtained  appeared  to  be  a pure  product,  melting  sharply  at  136#C  (uncorrected). 
Yield  23  grams  (84$  of  theoretical  quantity.) 

In  subsequent  experiments  it  was  found  that  the  chloromercuri-1- 
methylbenzofuran  was  also  obtained  in  good  yields  when  the  mercuric  chloride 
solution  was  made  somewhat  acid  with  HC1  (to  repress  HgClg  hydrolysis  and 
facilitate  its  solution)  before  addition  of  orthoallylphenol.  In  one  experiment 
in  which  the  mercuric  chloride  solution  was  made  acid  with  HC1  (about  2$)  and 
heated  on  water  bath  during  the  addition  of  orthoallyl  phenol,  the  precipitate 
consisted  in  part  of  a pink  product  which  was  less  soluble  in  the  hot  solution 
than  the  chlorcmereuri-l-methylbenzofuran.  This  pink  product  was  a powder  when 
dry  and  yielded  chloromercuri-l-methylbenzofuran.  It  appeared  to  consist, 
therefore,  of  the  initial  addition  product  of  ortho  allyl  phenol  and  mercuric 


chloride  according  to  the  equation: 

//Xnnch2-ch  =CH2  * 

OH  +HgCl2 


\CH2-CH  - CH2HgCl 
01 
'OH 


ICH-CH-CHpHgCl 
2 +HC1 


Preparation  of  Bromomercuri-l-methylbenzofuran 
3 grams  of  the  mercuric  acetate  derivative  of  ortho  allyl  phenol  were 
added  to  200  cc  of  an  aqueous  solution  containing  3 grams  potassium  bromide.  The 
mixture  was  warmed  on  the  water  bath  for  one  hour  and  allowed  to  stand  over  night 


. 

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13 


The  crystalline  precipitate  formed  was  filtered  off  and  dissolved  in  hot  alcohol 
from  which  it  crystallized  on  cooling.  The  pure  white  shiny  crystals  obtained 
were  filtered  off  and  dried.  Weight  2.7+  grains  or  about  90$  of  the  theoretical 


yield  of  the  bromide 


CH2-GH  -CHg-Hg-Br. 


These  crystals  melted  sharply  at  122#C  (uncorrected). 

The  analysis  of  these  crystals  for  mercury  content  gave  the  following 


results: 


Weight  of  sample  in  grams 
Stand.  Ag  NOg  solution  in  cc. 
Stand.  Na  CH  '»  " " 

N.P.  of  Ag  N6g  solution  0.02523 
N.P.  of  JJaCN  " 0.02599 

Mercury  in  per  cent 

Average 

Theoretical 


I 

0.4595 

7.1 

50.0 


II 

0.4040 

6.3 

44.0 


48.77  48.86 

48.81$  Eg 
48.50$  Hg 


Preparation  of  Mercuric  Sulphate  Derivatives  of  Ortho  Allyl  Phenol 
At  least  3 distinct  products  appear  to  have  been  obtained  by  the 
action  of  mercuric  sulphate  on  ortho  allyl  phenol.  The  normal  sulphate  cor- 


responding to  the  formula 


[f) 

CHgCH-CHjHg 

Lv 

-0 

J 

SO, 


was  obtained  as  follows: 


7 grams  of  mercuric  oxide  were  heated  with  5 grams  cone.  HgSO^  to  form  the 
mercuric  sulphate.  When  the  reaction  had  gone  to  completion  as  shown  by  a 
uniform  yellow  product,  200  cc  of  water  were  added.  The  mixture  was  heated  to 
boiling  and  just  enough  I^SO^  added  to  cause  complete  solution  of  the  mercuric 
sulphate.  9 grams  of  ortho  allyl  phenol  were  added  drop  by  drop,  and  with 
vigorous  stirring,  to  the  mercuric  sulphate  solution.  A solid  light  gray  pro- 
duct settled  in  the  bottom  of  the  flask. 

Several  attempts  were  made  to  purify  the  product,  the  best  results 
being  obtained  by  dissolving  in  hot  solutions  of  acetic  acid  or  dilute  HgSO^. 


1.  •>< 


. 


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14 

In  general,  the  solid  formed  on  cooling  was  an  amorphous  product,  hut  a solution 
containing  about  5 $ acetic  and  10$  sulphuric  acid  which  had  been  heated  to 
boiling  with  the  impure  mercuric  sulphate-rortho  allyl  phenol  addition  compound 
yielded  on  very  slow  cooling  nodules  of  a white  product*  These  nodules  were 
filtered  off,  washed  repeatedly  with  water  and  dried,  a total  of  about  one  gram 
of  pure  white  material  being  obtained.  It  did  not  melt  on  heating,  but  decom- 
posed suddenly  at  123*0.  It  hydrolysed  only  slowly  in  concentrated  hydrochloric 
acid,  yielding  ortho  allyl  phenol.  Its  analysis  for  mercury  content  gave  the 
following  results: 


Weight  of  sample  in  grams  0.3030 

Standard  Ag  NOg  solution  in  cc.  9.8 

" JffaCN  solution  in  cc.  40.0 

N.F.  of  Ag  NO3  solution  0.02523 
" NaCN  " 0.02599 

Mercury  in  per  cent  52.45 

Calculated  $ of  mercury  52.56 


During  the  attempts  at  purifying  the  original  addition  product  obtained, 
some  of  the  material  was  dissolved  in  a boiling  10$  solution  of  H2SO4,  and  a pink 
product  of  apparently  uniform  composition  separated  out  on  cooling.  It  was 
filtered  off,  washed  repeatedly  with  water  and  dried,  about  one  gram  of  amorphous 
powder  being  obtained.  This  powder  yielded  on  hydrolysis  a red  oil  which  was  not 
identified.  This  powder  also  decomposed  without  melting  at  about  180#C. 
analysis  gave  the  following  results  for  meroury  content: 


Weight  of  sample  in  grams  0.3675 

Ag  NOg  solution  in  cc.  6.8 

NaCN  " " 50.0 

N.F.  of  Ag  NOg  solution  0.02523 

" NaCN  " 0.02599 

Mercury  in  per  cent  61.56 


A third  mercuric  sulphate  - ortho  allyl  phenol  addition  product  pre- 
pared by  another  investigator  was  a light  gray  powder  somewhat  similar  to  the 
impure  product  obtained  in  the  first  preparation  described.  It  decomposed  without 
melting  at  about  137* C. 


. 

. 


15 


Reduction  of  Chloromercurl-l-methylbenzofuran 
to  form 

Dlbenzofuryl-l-methylmercury 

The  mercuric  chloride  - ortho  allyl  phenol  addition  compound  was  re- 
duced with  sodium  amalgam,  according  to  the  equation: 

Ha  amalgam 

2R  Hg  01 ^ R Hg  R + 2HaCl 

15  grams  of  the  recrystallized  chloromercuri-l-methylbenzofuran  were 
placed  in  a 200  oc  round  bottom  flask  and  100  cc  absolute  alcohol  added.  The 
flask  was  connected  with  a reflux  condenser  provided  with  a CaCl2  tube.  40 
grams  freshly  prepared  amalgam,  containing  4$  sodium,  were  added,  a few 
pieces  at  a time,  through  the  condenser.  The  flask  was  heated  very  gently  to 
start  the  reaction  and  to  keep  the  mixture  boiling  for  one-half  hour.  The  crys- 
tals of  the  mercuric  chloride-  ortho  allyl  phenol  addition  compound  had  all 
disappeared  at  the  end  of  that  time  and  a light  gray  precipitate  had  formed  in 
the  bottom  of  the  flask.  When  the  flask  was  cooled  on  ice,  no  chloro  mercuri-1- 
methylbenzofuran  crystallized  out,  which  indicated  complete  reduction  of  the 
above  product. 

The  precipitate  was  filtered  off,  and  found  to  consist  of  sodium 
chloride  with  a trace  of  impurities.  Its  weight  was  2.5  grams,  or  nearly  exactly 
that  of  the  theoretical  yield  of  Ha  Cl. 

Evaporation  of  the  alcoholic  solution  on  the  water  bath  yielded  a 
viscous  residue,  which  crystallized  only  with  difficulty.  Spontaneous  evapora- 
tion of  the  alcohol  yielded,  however,  nodules  of  white  crystals  together  with  a 
viscous  sticky  residue.  These  crystals  were  dissolved  in  ether,  a large  por- 
tion of  the  impurities  remaining  undissolved.  On  spontaneous  evaporation  of  the 
ether  somewhat  impure  crystals  again  separated  out.  These  crystals  melted  at 
88  - 90°C.  They  were  again  separated  twice  from  impurities  by  redissolving  in 


16 

ether  and  recrystallizing*  Pure  white  crystals  were  finally  obtained,  melting 
sharply  at  93*C  (uncorrected).  Yield:  6 gram3  of  pure  product  and  about  1 
gram  impure  material  or  about  50$  of  theoretical  yield.  Analyses  for  mercury 


content  gave  the  following  results: 

I 

II 

Weight  of  sample  in  grams 

0.4700 

0.41! 

A g UOg  solution,  in  cc. 

4.0 

2.4 

HaCH  " " 

42.55 

36.0 

N.F.  of  Ag  NOg  solution 

0.02523 

" HqCU  " 

0.02599 

Mercury  in  per  cent 

42.68 

42.76 

Average  42.82$  Hg 

Theoretical  42.98$  Hg 

3 grams  of  the  impure  dibenzofuryl-l-methylmercury,  obtained  by 
evaporating  the  alcoholic  solution  on  the  water  bath,  were  dissolved  in  50cc 
alcohol.  3 grams  red  mercuric  iodide,  dissolved  in  100  cc  alcohol  were  added 
to  the  above  solution  and  the  mixture  heated  on  the  water  bath,  the  flask  being 
provided  with  a reflux  condenser.  The  heating  was  continued  for  about  one  hour. 
Very  fine  white  crystals  formed  at  first,  but  larger  crystals  formed  after  some 
time,  a heavy  growth  settling  to  the  bottom  of  the  flask  after  a few  hours. 

3.5  grams  of  somewhat  impure  crystals  of  iodomercuri-l-methylbenzofuran  were  ob- 
tained. M.P.  112*0. 

The  above  results  would  seem  to  indicate  the  reaction: 
fi2  Hg  + Hg  I2  ► 2E  Hg  I 

but  when  attempts  were  made  to  repeat  the  experiment  using  pure  dibenzofuryl- 
l-methylmercury,  no  lodomercuri-l-methylbenzofuran  crystallized  out.  It  is 
thought  possible  that  the  impure  product  which  was  used  in  the  first  experiment 
contained  enough  ortho  allyl  phenol  so  that  its  reaction  with  mercuric  iodide 
furnished  enough  H I to  hydrolyse  the  dibenzofuryl-l-methylmercury  in  solution. 
The  fact  that  the  reduction  product  usually  obtained  from  chloromercuri-l-methyl 
benzofuran  contains  appreciable  quantities  of  ortho  allyl  phenol  would  tend  to 
confirm  this  assumption.  It  has  also  been  found  that  hydrolysis  of  dlbenzofuryl- 


. 

. 

. 

. 

. 

. 

. 

“ 

• 



. /< 


- ; 


■ 

. • i 


, 

- 

17 


1-methylmercury  produces  some  ortho  allyl  phenol,  although  strong  acid  is  required 
at  ordinary  temperature. 

Arsenic  Chloride  - Ortho  Allyl  Phenol  Addit ion  Product s 
In  the  initial  experiments  anhydrous  arsenic  chloride  and  dry  ortho 
allyl  phenol  were  mixed  in  various  proportions  and  kept  at  various  temperatures, 
but  no  apparent  reaction  took  place,  and  the  arsenic  chloride  and  ortho  allyl 
phenol  were  recovered  on  distillation.  Sdlutions  in  non-reactive  sol vents, such 
as  dry  benzene,  gave  the  same  results.  Catalysts  such  as  anhydrous  ferric  chlor- 
ide and  anhydrous  aluminum  chloride  reacted  with  the  phenol  group  and  could  not 
be  used. 


An  attempt  was  then  made  to  replace  the  Hg  Cl  group  in  chloromercuri- 
1-methylbenzofuran  by  As  Cl2^22^  as  follows: 

15  grams  of  recrystallized  chloromercuri-l-methylbenzofuran  and  50 
grams  of  anhydrous  arsenic  chloride  were  placed  in  a 100  cc  flask  provided  with 
a stopper  and  calcium  chloride  tube.  The  chloromercuri-l-methylbenzofuran  crystal 
were  quickly  replaced,  at  room  temperature,  by  a white  amorphous  precipitate, 
the  solution  taking  a lavendar  color  which  darkened  on  standing.  The  precipitate 
was  filtered  off  and  identified  as  mercuric  chloride.  Yield,  10  grams,  or 
practically  theoretical  quantity  for  complete  replacement  of  Hg  Cl  by  As  Cl2* 

The  filtrate  was  distilled  at  a pressure  of  20  mm  to  remove  the  excess  of  arsenic 
trichloride.  The  product  remaining  was  a dark  liquid,  rather  viscous,  which  de- 
composed when  attempts  were  made  to  distill  it  under  a pressure  of  20  mm. 

In  a second  experiment,  the  residue  remaining  after  distilling  off  the 
excess  of  arsenic  trichloride  was  refluxed  for  3 hours  with  5 % HaOH.  The  solution 
was  then  neutralized  with  acetic  acid  to  precipitate  any  of  the  arsenic  compound 

OCHg  -CH  -CH2-As«0  which  had  formed.  A very  viscous  yellow  liquid  was 


_ 


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18 


obtained.  This  product  becams  semi-solid  on  standing,  but  could  not  be  re- 
crystallized. 


19 


BIBLIOGRAPHY 


(1)  Einhorn  - Annalen  371.  131. 

German  Patents: 

172568  189335 

179627  194365 

180291  194748 

180292 

(2)  Adams  and  Karan  - J.A.C.S.  42,  1030. 

Cham.  Abstracts  L5,  412. 

U. 3. Patent  1,358,750. 

(3)  Kamm,  Adams  and  Volwiler  - U.S .Patent  1,358,751. 

(4)  Jenkins  - Thesis,  Univ.  of  Illinois,  1921. 

1 5)  Burnett  - " " " " " 

(6)  Peet  " " " " " 

(7)  Stoermer  and  Dzimski  - Ber.28j  11,2226. 

(8)  Riedel  - Friedlander  8^  1030. 

German  Patent  169819. 

(9)  Grignard  - Comptes  Rendus  130.  1322. 

132.  835. 

(10)  Ullmann  and  Munzhuber  - Ber.  36.404. 

(11)  Einhorn  - Eriedlander  8_,  995. 

German  Patent  179627 
U.S .Patent  812554 

(12)  Einhorn  - Friedlander  8,  994. 

(13)  Henry  - Comptes  Rendus  145.24. 

(14)  Tiffeneau  - Comptes  Rendus  134.  775. 

(15)  Sand  - Ber.  33,  2692. 

" 34,  1385 

Ann. 329.  135. 

(16)  Manchot  - Ber.  53,  984. 

Ann. 420.  170. 


. 


. 

. . 


V 


. ■ 


. 


, 

, . 

~ ; ■ 

, , 

. . 


. 

' » . . 


. 

• . • ' t V*  I & 


■ 

■ 


20 


(17)  Sperry  - Thesis,  Univ.  of  Illinois,  1922. 

(18)  Green  and  Price  - J.Chem.Soc.  119.  448. 

(19)  Claisen  - Ann.  401.29. 

(20)  Jacobs  - J.Amer.Chem.Soc.  39_,  2202. 

(21)  Adams  and  Hindfnsz  - J.Amer.Chem.Soc.  41,  654. 

(22)  Boeder  and  Bias!  - Ber.  4£,  2750. 


